The proposed research focuses on the neuropeptide amylin and its role in controlling for palatable food intake and body weight through action in the ventral tegmental area (VTA) of the mesolimbic reward system. FDA-approved amylin analogs for the treatment of Type II Diabetes Mellitus produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. While the literature has largely focused on the area postrema (AP) of the caudal brainstem as the primary site mediating the anorectic effects of amylin signaling, it is important to note that amylin receptors are also expressed in brain regions associated with reward and cognitive processes [e.g. VTA, nucleus accumbens (NAc)] and little-to-no investigation has been done to examine their contribution to energy balance control. Indeed, humans treated with an amylin analog report improved perceived control of eating and a 45% reduced risk of binge eating. Moreover, humans treated with amylin receptor agonists reduce their intake of highly palatable food more so than less-palatable food. Given that the excessive food intake contributing to obesity is driven, in part, by exposure to external stimuli associated with palatable food, it is of critical importance to investigate neurobiological systems that function to reduce excessive food seeking and consumption in response to food-related stimuli. It is also critical to evaluate the potential for amylin to interact with other physiological systes to produce an augmented reduction in food intake given that combination drug therapy holds greater promise than monotherapy for obesity treatment. Indeed, emerging basic science and clinical evidence shows that combined signaling by amylin and the adipose-tissue derived hormone leptin can lead to enhanced (potentially synergistic) suppression of food intake. Endogenous signaling by either leptin or amylin in the VTA is necessary for the normal control of food intake, thus highlighting the VTA as a potential neural locus mediating the amylin-leptin interaction. Experiments in this proposal will utilize novel approaches that combine behavioral, molecular, electrophysiological, electrochemical, neuropharmacological, genetic, and transgenic techniques to examine: [1] the neuronal and behavioral mechanisms mediating the role of endogenous VTA amylin receptor signaling in excessive feeding; [2] whether VTA amylin receptor signaling modulates NAc dopamine and NAc neural activity in response to food cues; [3] whether VTA processing mediates the food intake reducing interaction between amylin and leptin signaling. The research proposed will provide a novel framework for the development of more effective amylin-mediated treatment options for obesity.